This application is the translational component of an overall UO1 application entitled, Novel therapies in alcoholic hepatitis - University of Louisvill. Alcoholic hepatitis (AH) has a high morbidity and mortality. In VA Cooperative Studies in which liver biopsies were performed, only 35% of patients with AH and underlying cirrhosis, and 60% of those with AH alone (no cirrhosis) were alive at the end of four years, with most deaths occurring early in the study. There is no FDA-approved therapy for any stage of alcoholic liver disease (ALD). The most widely-used (off-label) drug therapies for AH are glucocorticoids and pentoxifylline. Both agents have anti-inflammatory activities and downregulate proinflammatory cytokines such as tumor necrosis factor (TNF). Unfortunately, an important subset of AH patients treated with glucocorticoids have steroid resistance, and some patients have contraindications to steroid therapy. Studies on pentoxifylline in AH are limited, and efficacy appears highest in preventing/treating the hepatorenal syndrome. Thus, new therapies as well as a better understanding of mechanisms/biomarkers for severity of disease and response to therapy are necessary. Our research team has been a leader in defining mechanisms of alcohol-induced liver injury using in vitro and animal models of ALD, and in translating basic findings into the clinical setting. Our group is the first to describe dysregulated cytokine metabolism in AH. We have a long-standing interest in mechanisms of inflammation and liver injury. We also have extensive experience in the gut-liver axis and AH, as well as in the development of novel therapies for AH.!!Building on the above translational research strengths of our program which focus on the gut-liver axis and inflammation in ALD, we propose three highly translational Specific Aims, which all relate to and utilize samples from our proposed UO1 clinical trial. Aim 1 will evaluate novel mechanisms for alcohol-induced alterations in gut integriy leading to endotoxemia and AH. We will study the therapeutic efficacy of both live probiotics and probiotic supernatants. Aim 2 will study the role of specific PDE4 inhibition in AH using animal models and our AH clinical patient population. There are recent data in the pulmonary literature showing that specific PDE4 inhibitors are effective in steroid resistant patients which may translate to AH. Lastly, Aim 3 evaluates mechanisms for steroid resistance using both specimens from patients in our clinical trial and in vitro data. All three of our specific aims utiize specimens obtained from our U01 clinical trial, and our protocol interacts with the two other translational protocols in our U01 consortium. Our goal is not only to better understand mechanisms for AH, but also to develop new therapies (including those already available for other diseases) for AH, either immediately transforming clinical practice or providing novel therapies for our clinical trial consortium. PUBLIC HEALTH RELEVANCE: This is a translational application portion of an overall UO1 application. Our goal is not only to better understand mechanisms for AH, but also to develop new therapies (including those already available for other diseases) for AH.